Osteoporosis is a disfiguring disease of older women that causes significant loss of independence and substantial morbidity and mortality. Excessive thyroid hormone, either endogenous or exogenous, may be associated with reduced bone mass and an increased risk of fracture. However, the magnitude and clinical significance of these associations are unknown and studies examining fracture risk using an objective measure of thyroid function have not been done. Thyroid dysfunction may alter the risk of fractures through mechanisms other than reduced bone mass, such as altered neuromuscular function or abnormal bone architecture. We propose a comprehensive study of the association of thyroid function, as assessed by serum TSH, and fractures, bone mass, and bone loss. We will use data already collected from the NIH-sponsored Study of Osteoporotic Fractures (SOF), the largest and most comprehensive prospective study of risk factors for osteoporotic fractures yet performed. In 1986, 9, 704 women were recruited for SOF from population-based listings in four US cities. Extensive data on multiple variables were collected at baseline, including historical information on hyperthyroidism and thyroid hormone use, and a serum sample was archived at -190 degree C. We will use an efficient nested case-cohort design: 450 women who have suffered fractures (150 vertebral fractures) since the initial exam will be compared to a random sample of 450 women from the cohort. We will measure ultra- sensitive third generation serum TSH levels on sera that was collected from subjects at baseline. We plan to test the hypotheses that low TSH levels, indicating abnormally high thyroid hormone levels, are associated with osteoporotic fractures, reduced bone mass, increased bone loss, and altered neuromuscular function. We will also examine the relationship between TSH and a newly developed technique which may assess bone quality, quantitative ultrasound (QUS). The proposed study will be the first large prospective study to examine the effects of thyroid function on bone mass, bone loss, and fractures in the same cohort. The cost of the proposed study is relatively small since it uses data and samples that have already been collected. The results of this study will help define the risks associated with excessive thyroid hormone, and contribute to our understanding of the mechanisms involved.